1. Field of the Invention
This invention relates to novel processes for preparing 1-butyl-2-[2'-(2H-tetrasol-5-yl)biphenyl-4-ylmethyl]-1H-indole-3-carboxyli c acid, an angiotensin II receptor antagonist. This invention also relates to novel intermediates useful in the synthesis of 1-butyl-2-[2'-(2H-tetrasol-5-yl)biphenyl-4-ylmethyl]-1H-indole-3-carboxyli c acid.
2. Description of the Field
The renin-angiotensin system is fundamental physiological mechanisms for regulating blood pressure in mammals. Angiotensinogen is secreted into the bloodstream by the liver. Angiotensinogen is then cleaved by the protease renin to yield the decapeptide angiotensin I, which in turn is hydrolysed by angiotensin converting enzyme (ACE) to the octapeptide angiotensin II.
Angiotensin I is inactive in the cardiovascular system, but angiotensin II has numerous effects. For example, angiotensin II stimulates the adrenal cortex to secrete aldosterone, which causes the kidneys to retain sodium and water, increasing blood pressure. Angiotensin II also causes arteriolar vasoconstriction and facilitates neurotransmission in the sympathetic nervous system. In addition to its effects on the cardiovascular system, angiotensin II contracts gastro-intestinal smooth muscle, produces glycogenolysis, alters renal function and produces various CMS effects. The effects of angiotensin II are mediated by the activation of specific angiotensin II receptors located in smooth muscle, adrenal medulla, brain, liver and kidney tissues. The angiotensin II receptor is presently delineated into two major subtypes (i.e., AT-1 and AT-2 receptor subtypes). Angiotensin II receptor antagonists, particularly those which selectively block AT-1 or AT-2 receptor subtypes, are useful in treating diseases which may be ameliorated by a decrease in the physiological effects of angiotensin II.
Various angiotensin II receptor antagonists are known. See, for example, U.S. Pat. Nos. 4,333,943, 4,880,804, 5,053,329, 5,124,335, and European Patents 0 245 637, 0 253 310, and 0 291 969, and also Wong et al. Hypertension 1990, 15, 459, J. Pharmacol. Exp. Ther. 1990, 256, 211, and Chiu et al., Biochem. Biophys. Res. Comm. 1989, 165, 196-203. Substituted indole compounds and derivatives thereof (e.g., 1-butyl-2-[2'-(2H-tetrasol-5-yl)biphenyl-4-yl-methyl]-1H-indole-3-carboxyl ic acid) are angiotensin II receptor antagonists and are disclosed as such in U.S. Pat. No. 5,212,195 and pending U.S. patent application Ser. No. 08/004,869.
The disclosures of these and other documents referred to throughout this application (e.g., in the Pharmacology section of the Detailed Description of the Invention) are incorporated in this application by reference.